Memory CD4 T-cells play a key role in host defense as well as the triggering and maintaining of inflammation. The triggering of the costimulatory signals plays a central role in the generation of effective immune responses. The costimulatory signals can be provided by a number of accessory molecules. Of the costimulatory molecules, CD29/VLA, CD26, and CD27 have been established by this group. CD29/VLA and CD26 are preferentially expressed on CD4 memory T-cells and play an important role in the costimulation, function, and migration of memory T-cells. Much remains to be clarified regarding the complex functions of CD29/VLA and CD26 in signal transduction and the subsequent effects upon T-cell function and cell migration. The major goal of this application is to determine the immunoregulatory circuits in man. The specific aims of this application are: 1) The molecular basis of CD29/VLA in T-cell costimulation, signaling and T-cell function. They will define the structural basis of Cas-L tyrosine phosphorylation and FAK activation and define the role of Cas-L in CD29/VLA-mediated cytokine production and gene expression. Moreover, the role of Cas-L in T-cell migration will be defined. 2) The molecular basis of CD26/DPPIV in T-cell function and costimulation. The role of CD26/DPPIV in T-cell migration, the precise characteristics of the binding of ADA to CD26, and the functional significance of ADA in T-cell activation will be defined. In addition, the structure and function of the ligand of CD26 other than ADA will be defined. 3), The molecular and cellular defects in patients with autoimmune diseases. Analysis of VLA-mediated costimulation in patients with autoimmune diseases will be performed. Moreover, the expression and function, of Cas-L, and FAK as well as the migratory activity of T-cells in autoimmune diseases will be determined. In addition, the level of CD26/DPPIV in serum/plasma and its correlation with clinical complications in autoimmune diseases will be defined. The study will not only provide new insights into understanding of the mechanisms of T-cell activation and migration, but will also provide new insights into understanding the precise molecular mechanisms of immune abnormalities found in various autoimmune diseases and will lead to the development of rational therapy for the manipulation of the abnormalities found in such diseases.